The objective of this proposal is to examine the dog as an animal model of Alzheimer's disease (AD). Several investigators have shown that Alzheimer's disease like neuropathology (ADLN) occurs in aged dogs.(1-10) Dogs have been reported to have preamyloid plaques, (1,5,6,7) senile amyloid plaques (2,3,9) and neurofibrillary tangles. (2,4) In preliminary work, our laboratory has examined the brains of beagle dogs which were raised in an environmentally controlled laboratory colony and found that the distribution of plaques in their brains was similar to that found in human AD(6). The animals studied did not receive any experimental treatment, and 58% were found to have plaque formations in their brains. Additionally, there is an apparent relationship between the litter a dog was born in and the occurrence of plaques in its brain at old age.(6) Thus, animals who had littermates with plaques were also found to have plaques, and those without plaques had littermates without plaques. The association of littermates and plaque formation suggests that canine plaque formation may be due to some prenatal influence, and may be genetic. The genetic hypothesis would be consistent with human data of autosomal dominant inheritance with age-dependent penetrance among relatives of patients with familial AD. (11) This proposal builds on these initial findings and will define the dog pathology more fully. The focus is on the examination of the dog as an animal model of ADLN. More specifically: 1) We will adapt human and rodent neurobehavioral tests of memory and sensory function to the dog to establish the degree of relationship between canine dementia and the presence of ADLN. 2) We will examine the brains from parents and offspring of dogs with established genetic histories to determine if the occurrence of plaques is genetically influenced. 3) We will examine brains from a variety of breeds of dogs to determine which breeds have the highest incidence of ADLN.